A phase 1/2 study of AU-007, a monoclonal antibody (mAb) that binds to IL-2 and inhibits CD25 binding, in patients with advanced solid tumors: Interim results.
Authors: Sophia Frentzas, Elizabeth Stephanie Ahern, Andrew James Weickhardt, Andrew Mark Haydon, Paul L. de Souza, John D. Powderly, Timothy Wyant, Jenny Tang, Lori Richards, Aron Knickerbocker, Inbar Amit, Yanay Ofran, James Robert Vasselli
Journal: Journal of Clinical Oncology (2023)

e14507 Background: AU-007 is a computationally designed mAb that binds to IL-2 on its CD25 binding epitope. AU-007 bound IL-2 (A/IL-2) cannot bind to trimeric (CD25, CD122, CD132) IL-2 receptors (IL-2R) on Tregs, vascular endothelium, or eosinophils, but IL-2’s binding to dimeric IL-2Rs (CD122, CD132) on T effector and NK cells is unhindered. AU-007 thus redirects endogenous or exogenous IL-2 (aldesleukin) towards T effector and NK cell activation, while diminishing immunosuppressive Treg activation and vascular leak. Unique in the IL-2 field, AU-007 can redirect endogenous IL-2 generated from A/IL-2 driven T effector cell expansion in vivo, converting a Treg-mediated autoinhibitory loop into an immune stimulating loop. A/IL-2 is expected to prolong the 85-minute T1/2 of IL-2, allowing endogenous IL-2 (as A/IL-2) or low dose aldesleukin to initiate an anti-tumor response. Methods: This first-in-human Phase 1 study consists of 3 dose escalation arms, each starting with one 1+2 cohort followed by 3+3 cohorts. Arm 1A evaluates escalating doses of monotherapy AU-007 (intravenous, every 2 weeks [Q2W]). Arm 1B evaluates AU-007 (Q2W) plus 1 loading dose of subcutaneous, low dose aldesleukin with the 1st AU-007 dose. The AU-007 dose will be fixed with escalating aldesleukin doses in sequential cohorts. Arm 1C evaluates AU-007 plus escalating doses of concomitant subcutaneous, low dose aldesleukin, both Q2W. The dose-limiting toxicity (DLT) evaluation period is the first 28 days of the 1st cycle. Tumor assessments by computed tomography scan occur with each 8-week cycle. The AU-007 and aldesleukin dose and schedule for Phase 2 expansion will be based on safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD). Results: As of 01 February 2023, 8 patients have been enrolled into the first 3 Cohorts of Arm 1A (0.5, 1.5, and 4.5 mg/kg AU-007). AU-007 was well tolerated with no DLTs and all treatment-related adverse events were Grade 1. These occurred in 3 patients, 1 at each dose level. The 4th Cohort of Arm 1A (9 mg/kg AU-007) and the 1st Cohort of Arm 1B (4.5 mg/kg AU-007 + 1 aldesleukin dose of 15,000 IU/kg) are now being evaluated. Three of 4 tumor evaluable patients had a best response of stable disease and 2 continue treatment. Two patients discontinued with objective progression and one with clinical progression. Initial PK data (0.5 and 1.5 mg/kg) demonstrate dose proportional AU-007 serum concentrations with typical characteristics of an IgG1 human mAb. All 7 patients with available PD data demonstrate overall decreasing Tregs (% change and absolute) and eosinophils, which both express the trimeric IL-2 receptor. Conclusions: AU-007 monotherapy at doses up to 4.5 mg/kg Q2W is safe and well tolerated, with initial signs of immune modulation consistent with AU-007’s mechanism of action. These findings warrant continued escalation and combination with aldesleukin. Clinical trial information: NCT05267626 .